1. Field of the Invention
This invention relates to new therapeutically useful quinazoline derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to methods of providing a selective immunosuppressive effect in the control or prophylaxis of immune complex diseases such as rheumatoid arthritis.
2. Description of the Prior Art
Evidence is accumulating that dysfunctional immune mechanisms play a major role in a number of diseases characterized by tissue damage. One group of such diseases is termed the immune complex diseases and includes such diseases as rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Reiters syndrome, systemic lypus erythematosis, scleroderma, polymyositis, dermatomyositis, polyarteritis (including necrotizing arteritis), amyloidosis, Sjogren's syndrome, acute and chronic glomerulonephritis, autoimmune hemolytic anemia and relapsing polychondritis. Such chronic ailments are believed to involve a defect in host defense mechanisms which results in the formation of injurious immune complexes. These immune complexes set off a chain of events in the involved joint or tissue leading to inflammation, pain and, in severe circumstances, to disablement and even death.
Current drug therapy of rheumatoid arthritis is largely symptomatic, with primary emphasis on use of mild anti-inflammatory drugs, e.g. phenylbutazone, ibuprofen, naproxen, fenoprofen, etc. These compounds have little or no effect on the underlying disease which in many cases steadily progresses to the point of joint destruction. The use of potentially more effective agents such as the corticosteroids is limited by their severe side effects. Clearly there is a need for additional drugs for the treatment of rheumatoid arthritis which are effective and yet do not possess the serious adverse side effects of presently available agents. In particular, there is a need for drugs which are capable of inhibiting basic mechanisms underlying the initiation and progression of the disease and which are capable of arresting and even reversing the disease process.
As noted above, the immune complex group of diseases is believed to result from defects in the immune defense system. The immune defense system of a human or other warm-blooded animal is composed of two parts, both of which involve specialized lymphocytes which are stimulated to respond to an inciting antigen. One part, the cell-mediated (cellular immunity) arm, involving the direct participation of thymus dependent lymphocytes (T-cells), provides the major protection against intracellular pathogens, including a number of bacteria, most viruses, fungi and protozoa. It is also important in the transplantation rejection reaction and in the maintenance of a surveillance system for the elimination of cancer cells. The other part, the humoral (antibody-mediated) arm, involving thymus independent lymphocytes (B-cells) which can differentiate into antibody producing plasma cells, also plays an important role, especially in establishing long term immunity to many pathogens. A normal immune response results in the elimination of the offending antigen without tissue damage. In the immune complex diseases, however, there appears to be a breakdown in regulated antigen recognition such that antibodies (autoantibodies) and T-cells are produced which also react with altered components (antigens) of the host's own tissues producing immune complexes, with the resulting complexes leading to the tissue damage characteristic of these diseases.
A rational approach to the treatment of the immune complex diseases is to try to suppress the abnormal production of antibodies, i.e., to suppress the humoral immune response. Currently available immunosuppressive agents such as cyclophosphamide and azathioprine have been shown to be at least partially effective in treating rheumatoid arthritis and other immune complex diseases. These compounds, however, are capable of suppressing both the humoral and cellular immune responses, thus seriously impairing host resistance to infection and potentially increasing the risk of cancer.
It is an object of the present invention to make available a compound which will selectively suppress the humoral immune response believed primarily responsible for the immune complex diseases without suppressing or impairing the cellular immune response with its vital regulatory and host defense mechanism roles. It is a further object of the present invention to provide a selective immunosuppressant which will be effective in the prophylactic and therapeutic treatment of rheumatoid arthritis and other immune complex diseases. A further object is to provide such a selective immunosuppressant which is orally effective.
With respect to the novel quinazoline derivatives of the present invention, the prior art discloses the compounds 2-(4-chloroanilino)quinazolin-4(3H)-one (formula II below) and 2-(4-chloroanilino)-4-methylthioquinazoline (formula III) in J. Chem. Soc., 775, (1947). No pharmacological utility is indicated for either compound. ##STR2##